Proteinases from polymorphonuclear leukocytes and macrophages, especially elastases (human leukocyte elastase and cathepsin G), appear to be responsible for the chronic tissue destruction associated with inflammation, arthritis and emphysema. During infection or inflammation the normal lung is protected from proteolytic digestion by the protease inhibitor a.sub.1 -antitrypsin. The protective mechanism appears to be non-operative in individuals with an a.sub.1 -antitrypsin deficiency due to genetic or other causes. Synthetic elastase inhibitors capable of replacing a.sub.1 -antitrypsin therefore appear to be useful in the treatment of pulmonary emphysema and related diseases.
Several types of elastase inhibitors have been reported in the literature. These include peptide chloromethyl ketones as described in "Inhibition of Human Leukocyte Elastase by Peptide Chloromethyl Ketones", P. M. Tuhy and J. C. Powers, FEBS Letters, 50, 359-61 (1975); "Specificity of Porcine Pancreatic Elastase, Human Leukocyte Elastase and Cathepsin G. Inhibition with Peptide Chloromethyl Ketones", J. C. Powers, B. F. Gupton, A. D. Harley, N. Nishino and R. J. Whitley, Biochem. Biophys. Acta. 485, 156-66 (1977); azapeptides "Proteinase Inhibitors. 1. Inhibitors of Elastase", C. P. Dorn, M. Zimmerman, S. S. Yang, E. C. Yurewicz, B. M. Ashe, R. Frankshun and H. Jones, J. Med. Chem., 20: 1464-68 (1977); "Reaction of Serine Proteases with Aza-amino Acid and Aza-peptide Derivatives", J. C. Powers and B. F. Gupton, Meth. Enzymol., 46: 208-16 (1977); sulfonyl fluorides "Specificity and Reactivity of Human Leukocyte Elastase, Porcine Pancreatic Elastase, Human Granulocyte Cathepsin G, and Bovine Pancreatic Elastase, Human Granulocyte Cathepsin G, and Bovine Pancreatic Chymotrypsin with Arylsulfonyl Fluorides"; "Discovery of a new series of potent and specific irreversible Elastase Inhibitors", T. Yoshimura, L. N. Barker and J. C. Powers, J. Biol. Chem., 257, 5077-84 (1982-); heterocyclic acrylating agents "Inhibition of Elastase and Other Serine Proteases by Heterocyclic Acylating Agents", M. Zimmerman, H. Morman, D. Mulvey, H. Jones, R. Frankshun and B. M. Ashe, J. Biol. Chem., 255: 9848-51 (1980); "Selective Inhibition of Human Leukocyte Elastase and Bovine a.sub.i -Chymotrypsin by Novel Heterocycles", B. M. Ashe, R. L. Clark, H. Jones and M. Zimmerman, J. Biol. Chem., 256: 11603-6 (1981); imidazole N-carboxamides, W. C. Groutas, R. C. Badger, T. D. Ocain, D. Felker, J. Frankson and M. Theodorakis, Biochem. Biphys. Res. Commun., 95: 1890 (1980); and p-nitrophenyl-N alkyl carbamates, "p-Nitrophenyl Carbamates as Active-Site-Specific Reagents for Serine Proteases", R. E. Scofield, R. P. Werner and F. Wold, Biochemistry, 16: 2492 (1977).
Although some peptide chloromethyl ketones have been shown to be effective in preventing elastase induced emphysema in animal models there is considerable question whether such reactive agents could be used for treating emphysema in humans. ("Prevention of Elastase Induced Experimental Emphysema by Oral Administration of a Synthetic Elastase Inhibitor," A. Janoff and R. Dearing, Am. J. Respir. Dis., 121: 1025-3 (1980)). This is not surprising since the alkylating moieties in these inhibitors might render them toxic when used on a continuous basis. To be suitable for human use, an enzyme inhibitor has to show a high degree of selectively and must have minimal toxic side effects. As a result, most drugs are molecules that reversibly bind to specific enzymes or receptor sites. Examples are the carbamate esters physostigmine and neostigmine which have been clinically used as inhibitors of acetyl choline esteraces, A. G. Gilman, L. S. Goodman and A. Gilman, "The pharmacological Basis of Therapeutics", p. 101, MacMillan Publishing Co. (1980).
A series of peptide elastase inhibitors were disclosed in U.S. Pat. No. 4,643,991 to Digenis et al. Another group of polymer-bound elastase inhibitors was disclosed in U.S. application Ser. No. 242,294 by Digenis et al. filed on Sep. 9, 1988, now U.S. Pat. No. 5,162,307, issued Nov. 10, 1992. Still other peptidyl carbamate inhibitors of the enzyme elastase were disclosed in U.S. application Ser. No. 07/263,385 entitled "Novel Peptidyl Carbamate Inhibitors of the Enzyme Elastase" by Digenis et al., filed on Oct. 27, 1988, now U.S. Pat. No. 5,008,245, issued Apr. 16, 1991. The latter Digenis application also provides methods of inhibiting the enzyme elastase with the peptidyl carbamate agents described therein. The contents of the Digenis et al patent and applications referenced above are incorporated herein by reference to the extent that they enable the specific HLE inhibitory agents described therein and their methods of preparation.
Various conditions of the eye are known to be associated with corneal scarring and fibroblast proliferation, amongst them ocular coagulation and burns, mechanical and chemical injury, ocular infections such as kerato-conjunctivitis, and other ocular conditions. Some of these conditions are known to arise post-operatively after surgical treatment of other ocular conditions. This undesirable tissue growth is easily neovascularized and therefore becomes permanently established and irrigated. Tissue scarring or fibroblast proliferation is a condition which is difficult to treat. Presently, it is treated by subjecting the ocular area to further surgery or by using steroids, topically or by injection. However, steroids do increase side effects such as infection, cataract and glaucoma. Other non-steroidal agents like indomethcin have very little anti-scarring effects. (Williamson J. et al., British J. of Ophthalmology 53:361 (1969); Babel, J., Histologie Der Crtisonkatarakt, p.327. Bergmann, Munich (1973)).
Even after further surgery the proliferation of fibroblastic tissue continues to occur and further scar tissue appears. Thus, in addition to surgery being an extremely invasive procedure, the results attained thereof are not entirely satisfactory.
Accordingly, there remains a need in the art for methods of reducing and/or preventing the formation of corneal scar tissue or fibroblast proliferation which are not subject to the disadvantages of methods known in the art for this purpose.